International Journal of Pharmaceutics 418 (2011) 6–12

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International Journal of Pharmaceutics

journal homepage: www.elsevier.com/locate/ijpharm

Review

Higuchi equation: Derivation, applications, use and misuse

Juergen Siepmann a,b,∗ , Nicholas A. Peppas c,d,e
a
Univ. Lille Nord de France, College of Pharmacy, 3 Rue du Professeur Laguesse, 59006 Lille, France
b
INSERM U 1008, Controlled Drug Delivery Systems and Biomaterials, 3 Rue du Prof. Laguesse, 59006 Lille, France
c
The University of Texas at Austin, Department of Chemical Engineering, 1 University Station C0400, Austin, TX 78712-0231, USA
d
The University of Texas at Austin, Department of Biomedical Engineering, 1 University Station C0400, Austin, TX 78712-0231, USA
e
The University of Texas at Austin, Division of Pharmaceutics, 1 University Station C0400, Austin, TX 78712-0231, USA

a r t i c l e i n f o a b s t r a c t

Article history: Fifty years ago, the legendary Professor Takeru Higuchi published the derivation of an equation that
Received 9 February 2011 allowed for the quantification of drug release from thin ointment films, containing finely dispersed drug
Received in revised form 20 March 2011 into a perfect sink. This became the famous Higuchi equation whose fiftieth anniversary we celebrate
Accepted 22 March 2011
this year. Despite the complexity of the involved mass transport processes, Higuchi derived a very simple
Available online 31 March 2011
equation, which is easy to use. Based on a pseudo-steady-state approach, a direct proportionality between
the cumulative amount of drug released and the square root of time can be demonstrated. In contrast
Keywords:
to various other “square root of time” release kinetics, the constant of proportionality in the classical
Higuchi
Modeling
Higuchi equation has a specific, physically realistic meaning. The major benefits of this equation include
Diffusion the possibility to: (i) facilitate device optimization, and (ii) to better understand the underlying drug
Controlled drug release release mechanisms. The equation can also be applied to other types of drug delivery systems than thin
Drug release mechanism ointment films, e.g., controlled release transdermal patches or films for oral controlled drug delivery.
Later, the equation was extended to other geometries and related theories have been proposed. The aim
of this review is to highlight the assumptions the derivation of the classical Higuchi equation is based on
and to give an overview on the use and potential misuse of this equation as well as of related theories.
© 2011 Elsevier B.V. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
2. Derivation of the Higuchi equation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
3. Fickian diffusional release from a thin polymer sample . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
4. Misunderstandings and misuse of the Higuchi and related equations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
5. Drug delivery from swellable systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

1. Introduction in their utility during both the design stage of a pharmaceutical

formulation and the experimental verification of a release mecha-
One of the most important and challenging areas in the drug nism (Peppas, 1984a,b; Harland et al., 1988a; Siepmann et al., 2006;
delivery field is to predict the release of the active agent as a Siepmann and Siepmann, 2008).
function of time using both simple and sophisticated mathemat- In order to identify a particular release mechanism, experimen-
ical models (Gurny et al., 1982; Korsmeyer and Peppas, 1983a; tal data of statistical significance are compared to a solution of the
Korsmeyer et al., 1983; Peppas, 1983; Peppas and Franson, 1983; theoretical model. It is therefore clear that only a combination of
Franson and Peppas, 1983). The importance of such models lies accurate and precise data with models accurately depicting the
physical situation will provide an insight into the actual mecha-
nism of release (Korsmeyer and Peppas, 1983b; Peppas, 1984c,d;
∗ Corresponding author at: Univ. Lille Nord de France, College of Pharmacy,
Lustig and Peppas, 1985; Siepmann and Peppas, 2000).
INSERM U 1008, 3 Rue du Professeur Laguesse, 59006 Lille, France.
The vast majority of theoretical models is based on diffusion
Tel.: +33 3 20964708; fax: +33 3 20964942. equations (Ritger and Peppas, 1987a,b; Siepmann and Peppas,
E-mail address: juergen.siepmann@univ-lille2.fr (J. Siepmann). 2001; Siepmann and Goepferich, 2001). The phenomenon of

0378-5173/$ – see front matter © 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.ijpharm.2011.03.051
 J. Siepmann, N.A. Peppas / International Journal of Pharmaceutics 418 (2011) 6–12
diffusion is intimately connected to the structure of the material
through which the diffusion takes place thus the morphology of the
polymeric materials should be accounted for in a successful model
(Peppas and Gurny, 1983; Franson and Peppas, 1983; Gurny et al.,
1983; Lustig and Peppas, 1984; Harland et al., 1988b; Peppas and
Sahlin, 1989). There has been a limited number of reviews that have
addressed these aspects of controlled release formulations. The
mechanisms of drug release offer a convenient way to categorize
controlled release systems into: (i) diffusion-controlled (Peppas
and Lustig, 1985; Peppas and Segot-Chicq, 1985); (ii) swelling-
controlled (Korsmeyer et al., 1982; Peppas et al., 1984; Davidson
and Peppas, 1984, 1985; Peppas, 1987); and (iii) chemically con-
trolled.
While the Higuchi equation addressed important aspects of drug
transport and release from planar devices, it has been misinter-
preted and misused in many occasions. It is instructive to return
to the original derivation and examine how Higuchi’s and other
“popular” release equations were developed.
2. Derivation of the Higuchi equation
In his seminal contribution Takeru Higuchi considered the
release of a drug from a thin ointment film into the skin (Higuchi,
1961). He considered the following conditions:
(1) Drug transport through the ointment base is rate limiting,
whereas drug transport within the skin is rapid.
(2) The skin acts like a “perfect sink”: The drug concentration in
this compartment can be considered to be negligible.
(3) The initial drug concentration in the film is much higher than
the solubility of the drug in the ointment base.
(4) The drug is finely dispersed within the ointment base (the size
of the drug particles is much smaller than the thickness of the
film).
(5) The drug is initially homogeneously distributed throughout the
film.
(6) The dissolution of drug particles within the ointment base is
rapid compared to the diffusion of dissolved drug molecules
within the ointment base.
(7) The diffusion coefficient of the drug within the ointment base
is constant and does not depend on time or the position within
the film.
(8) Edge effects are negligible: The surface of the ointment film
exposed to the skin is large compared to its thickness. The math-
ematical description of drug diffusion can be restricted to one
dimension.
(9) The medium (ointment base) does not swell or dissolve during
drug release.
Under these conditions, Higuchi could derive his surprisingly
simple equation, allowing for the quantification of drug release
from this rather complex type of drug delivery system. The basic
ideas of the derivation of this famous equation are detailed in the
following.
Upon exposure to perfect sink conditions, drug molecules dis-
solved in the ointment base diffuse into the skin. Initially, this
occurs only close to the surface of the ointment film. Since drug
dissolution is rapid and a large excess of drug is provided, the
molecules that leach out of the system are rapidly replaced by the
(partial) dissolution of non-dissolved drug particles located in this
region. Thus, the concentration of dissolved drug molecules within
the ointment base remains constant as long as non-dissolved drug
excess is provided (saturated solution). Only when all drug parti-
cles located in the region next to the surface are finally dissolved,
the concentration of dissolved drug molecules in this region falls
7
Fig. 1. Schematic presentation of the drug concentration–distance-profile within
the ointment base after exposure to perfect sink conditions at time t (solid line) and
at time t + dt (dashed line). The variables have the following meanings: cini and cs
denote the initial drug concentration and drug solubility, respectively; h represents
the distance of the front, which separates ointment free of non-dissolved drug excess
from ointment still containing non-dissolved drug excess, from the “ointment-skin”
interface at time t; dh is the distance this front moves inwards during the time
interval dt.
below saturation concentration. Due to concentration gradients
subsequently also dissolved drug molecules located further away
from the film’s surface diffuse through the ointment base into the
skin. Importantly, the concentration of dissolved drug molecules
in this newly concerned region remains constant (saturation con-
centration) as long as non-dissolved drug excess is provided in that
region.
After a given time t, the drug concentration–distance-profile
represented by the solid line in Fig. 1 is obtained in the ointment
film. On the y-axis, the drug concentration is plotted, on the x-axis
the distance. The diagram can be seen as a cross-section through
the ointment film and the skin (located on the right hand side and
providing perfect sink conditions). Note that only for visibility rea-
sons the illustrated drug solubility, cs , is relatively high compared
to the initial drug concentration cini . Ideally, cini should be much
larger than cs (by a factor of 10 or more). As it can be seen, parts of
the ointment have been depleted of drug at this time point (illus-
trated by the dotted area). At a certain distance from the surface
a sharp front can be observed, at which the drug concentration
steeply increases from saturation concentration to “initial concen-
tration”. This front separates the part of the ointment, which still
contains non-dissolved drug particles (left hand side) and the part
of the ointment, which is free of non-dissolved drug excess (right
hand side). This front is located at the distance h from the film’s sur-
face and is sometimes called “diffusion front”. In order to be able
to calculate the amount of drug released from the ointment film
at this time point t, the drug concentration–distance-profile within
the part of the ointment depleted of drug excess must be known.
In order to describe the drug concentration gradient in the oint-
ment zone located between the “diffusion front” and the skin,
Higuchi used a pseudo-steady-state approach, which is valid for sys-
tems containing initially a large excess of drug (drug loading  drug
solubility). The idea is the following: If the initial drug concen-
tration is much higher than drug solubility in the ointment base
(ideally, by factor 10 or more), it takes a long time to dissolve all
drug excess at the distance h from the film’s surface. Thus, the
concentration at this position can be considered constant during
a certain time period. In addition, perfect sink conditions are pro-
vided at the film’s surface. Since the ointment base does not swell or
dissolve, pseudo-steady-state conditions are provided for drug dif-
fusion: a saturated drug solution on the one hand side, perfect sink
on the other hand side and a constant distance in-between. Using
Fick’s second law of diffusion, it can be shown that under these
conditions, the drug concentration–distance-profile between the
surface of the film and the “diffusion front” is linear (solid line in
8 J. Siepmann, N.A. Peppas / International Journal of Pharmaceutics 418 (2011) 6–12
Fig. 2. Surfaces indicative for the amounts of drug released from the ointment base
at time t (dotted trapezoid) and at time t + dt (dashed trapezoid + dotted trapezoid).
The variables have the following meanings: cini and cs denote the initial drug con-
centration and drug solubility, respectively; h represents the distance of the front,
which separates ointment free of non-dissolved drug excess from ointment still con-
taining non-dissolved drug excess, from the “ointment-skin” interface at time t; dh
is the distance this front moves inwards during the time interval dt.
Fig. 1). Consequently, the amount of drug released from the oint-
ment film at time t can be represented by dotted trapezoid in Fig. 1.
It has to be pointed out that under non-pseudo-steady-state con-
ditions, the drug concentration gradient in the ointment zone free
of drug excess is not linear and the resulting geometries are much
more complicated.
Fig. 2 focuses on the dotted trapezoid representing the amount
of drug released from the film at time t. Note that only a cross-
section of the ointment film is illustrated in Figs. 1 and 2. Thus,
the surface of the dotted trapezoid corresponds to the cumulative
amount of drug released divided by the surface area of the film
exposed to the skin, A. Due to the very simple geometry, it can
easily be shown that the cumulative amount of drug released from
the ointment film at time t, Mt , can be calculated as follows:
Mt
 cs
 time” release kinetics. However, it has to be pointed out that the
= h cini − (1)
A 2
However, for the use of this equation h must be known. In order to
express h as a function of other variables, Takeru Higuchi consid-
ered the drug concentration–distance-profile within the ointment
film a certain time period (dt) later: at time t + dt. The dashed line
in Fig. 1 illustrates this situation: The “diffusion front” separating
ointment free of drug excess and ointment still containing drug
excess moved the distance dh away from the surface. Importantly,
the drug concentration gradient between the new front position
h + dh and the skin can again be considered linear, due to the
high excess of drug (compared to the drug’s solubility) and the
pseudo-steady-state approach described above. Consequently, the
cumulative amount of drug released per unit surface area dM/A
in the time interval dt can be represented by the dashed trapezoid
illustrated in Fig. 2. Again, due to the given, very simple geometries,
it can easily be shown that:
dM cs
= cini dh − dh (2)
A 2
In addition, Fick’s 1st law of diffusion (Fick, 1855) can be used in
order to quantify the amount of drug released from the ointment
film in the time interval dt (considering a saturated drug solution
at distance h from the surface and perfect sink conditions):
dM cs
= AD (3)
dt h
Importantly, combining Eqs. (2) and (3) allows to obtain the
following expression for h:

D t cs
h=2 (4)
2 cini − cs
Substituting Eq. (4) into Eq. (1) and simplifying leads to:
Mt 
= (2cini − cs )Dtcs (5)
A
For a high initial excess of drug (cini  cs ), this equation can
further be simplified to:
Mt 
= 2 cini D cs t (6)
A
This is the classical Higuchi equation.
Obviously, one cannot violate the conditions on which Higuchi’s
derivation of his famous equation is based. In particular, the
pseudo-steady-state approach needs to be valid, requiring a high
initial excess of drug and a stationary “ointment–skin” interface (no
swelling, no ointment base dissolution).
Obviously, the classical Higuchi equation can also be used to
describe drug release from other controlled drug delivery systems
than ointment films, e.g., thin patches for transdermal drug deliv-
ery or thin films for oral drug delivery. In the latter case, generally
the two planar surfaces of the system are exposed to the release
medium, which is a stirred bulk fluid (instead of skin). The Higuchi
equation has later been extended to other geometries (e.g., Higuchi,
1963; Roseman and Higuchi, 1970). The reader is referred to the
article of Lee of this special issue for more details (Lee, this issue).
Note that Eq. (6) can also be written in the following, more
general form:
√
Mt = k t (7)
with

k=A 2 cini D cs (8)
Thus, the classical Higuchi equation describes a “square root of
constant k has a very specific and physically realistic meaning in
the case of the Higuchi equation (Eq. (8)). Unfortunately, this is not
always taken into account and in some reports the classical Higuchi
equation is confused with other types of square root of time release
kinetics. It has to be highlighted that other types of controlled
drug delivery systems, which are governed by release mechanisms
different from those considered by Higuchi can also be character-
ized by a proportionality between the cumulative amount of drug
released and time. One example is described in the following.
3. Fickian diffusional release from a thin polymer sample
It is now instructive to consider also the simple derivation of a
general solution of the diffusion equation for transport and release
of drug from a one-dimensional object, in which the drug is initially
homogeneously distributed at a concentration below the maximum
solubility limit.
We consider one-dimensional, isothermal drug transport and
diffusional release from a thin slab of a hydrophilic or hydrophobic
polymer film or sheet of thickness L where the structure is ini-
tially maintained at a constant uniform drug concentration c0 , and
perfect sink conditions are provided at the surfaces. This situation
corresponds to the typical experimental conditions for a release
experiment. For an assumed constant drug diffusion coefficient D
 J. Siepmann, N.A. Peppas / International Journal of Pharmaceutics 418 (2011) 6–12 9

with one-dimensional diffusion in the x direction, Fick’s second law, Table 1

Different forms of non-constant diffusion coefficients (the variables are defined in
along with the appropriate initial and boundary conditions, may be
the text).
written as:
Type of carrier Eq. Form of Dip
∂c ∂2 c
=D 2 (9) Porous 16 Dip = 2 v
∂t ∂x 6
ε
Porous 17 Deff = Diw Kp Kr 
where Dip 2
Microporous 18 = (1 − ) (1 + ˛ + ˇ3 + 5 )
t=0 − L/2 < x < L/2 c = c0 (10)
Db
 
Nonporous 19 Dip = Do exp − vk
t > 0 x = ±L/2 c = 0 (11) D2,13
 qs   1 
f

Nonporous 20 = ϕ(qs ) exp −B −1

  f,1 2 
D2,1 V H

The solution to Fick’s law in the form of a trigonometric series D2,13 M̄c −M̄c∗ k r
Nonporous (highly swollen) 21 = k1 exp − Q2−1s
D2,1 M̄n −M̄c∗
under the above specified conditions is (Crank, 1975):
 ∞  
Mt 8 (2n + 1)2 · 2
=1− · exp − ·D·t (12) A selective summary of the various forms of the diffusion coef-
M∞ (2n + 1)2 · 2 L2
ficient is provided in Table 1.
n=0
One of the earliest approaches of estimating the diffusion coef-
where Mt is defined as the amount of drug released at time t, and
ficient through a polymer carrier is that of Eyring (1936). In this
M∞ is the amount of drug released as time approaches infinity. An
theory, diffusion of a solute through a medium is presented as a
alternate solution to Eq. (12) that is useful for interpretation of short
series of jumps instead of a continuous process. Therefore, in Eq.
time behavior is given in the form of an error function series:

(16) in Table 1, which comes from the Eyring analysis,  is the dif-
Mt Dt
 1/2 1 
∞
nL fusional jump of the drug in the polymer and v is the frequency of
n
=4 2 +2 (−1) ierfc √ (13) jumping.
M∞ L 1/2 2 Dt
n=1 Fujita (1961) utilized the idea of free volume in polymers to
estimate the drug diffusion coefficient and arrived at an exponen-
where ierfc x represents the integrated complementary error func-
tial dependence of the drug diffusion coefficient on the free volume,
tion of x. For ‘small’ times, Eq. (13) can be approximated by:
uf , which is given by Eq. (19) in Table 1. Yasuda and Lamaze (1971)
Mt Dt
 1/2 refined the Fujita’s theory and presented a molecularly based the-
=4 (14)
M∞ L2 ory, which predicts the diffusion coefficients of drugs through a
polymer matrix rather accurately (Eq. (20)). In their treatment the
As indicated by Eq. (14), Fickian diffusion in a thin polymer sam-
normalized diffusion coefficient, the ratio of the diffusion coeffi-
ple is characterized by an initial tl/2 -time dependence of the drug
cient of the solute in the polymer, D2,13 , to the diffusion coefficient
transport. The short time approximation is valid for the first 60% of
of the solute in the pure solvent, D2,1 , is related to the degree of
the total drug release.
hydration, H, and free-volume occupied by the swelling medium,
So, whether drug delivery is approached by the Higuchi equation
Vf,1 . In addition, ϕ is a sieving factor which provides a limiting
or by the simple release from a polymer film using pure Fickian
mesh size impermeable to drugs with cross-sectional area qs , and
diffusion, the principal result is a tl/2 -time dependence of the drug
B is a parameter characteristic of the polymer. In Eq. (20), the sub-
transport.
scripts 1, 2 and 3 refer to the swelling medium, drug and polymer,
respectively.
4. Misunderstandings and misuse of the Higuchi and
Peppas and Reinhart (1983), Reinhart and Peppas (1984) and
related equations
Peppas and Moynihan (1985) also developed a theoretical model
based on a free volume of the polymer matrix. In their theory they
Several important assumptions have been implicitly incorpo-
assumed the free volume of the polymer to be the same as the
rated in Eqs. (9)–(12). First, these equations describe the release of
free volume of the solvent and they arrived at Eq. (21) in Table 1.
a drug from a carrier of a thin planar geometry, equivalent equa-
They related the normalized diffusion coefficient to the degree
tions for release from thick slabs, cylinders, and spheres have been
of swelling, Q, the solute radius, rs , and the molecular weight of
derived (Baker, 1987). It should also be emphasized that in the
the polymer chains. More specifically, M̄c is the average molec-
above written form of Fick’s law the diffusion coefficient is assumed
ular weight of the polymer chains between adjacent crosslinks
to be independent of concentration. This assumption, while not
(Fig. 3), M̄n is the average molecular weight of the linear poly-
conceptually correct, has been largely accepted due to the com-
mer chains prepared under identical conditions in the absence
putational simplicity.
of the crosslinking agent, and M̄c∗ is the critical molecular weight
Initial and boundary conditions, which are necessary for solving
between crosslinks below which a drug of size rs could not diffuse
Eq. (9), allow for the appropriate description of the experimental
through the polymer network. In addition, k1 and k2 are constants
conditions imposed upon the drug release device. The solutions of
related to the polymer structure. This theory is applicable to drug
Eq. (9) are subject to a number of boundary conditions that can be
transport in highly swollen, nonporous hydrogels. Equations for
applied to various in vitro and ex vivo experiments.
moderately or poorly swollen (Peppas and Moynihan, 1985) and
In order to improve the predictive power of the Fickian diffu-
semi-crystalline hydrogels (Harland and Peppas, 1989) were also
sion theory, a concentration dependent diffusion coefficient can be
developed.
used in Fick’s law. The latter is then rewritten and solved with the
Yet, another approach for the prediction of the diffusion coef-
appropriate boundary conditions:
ficient of a drug in a controlled-release device has been adopted
 
∂ci ∂ ∂ci from the chemical engineering field. More specifically, the trans-
= Dip (ci ) (15) port phenomena in porous rocks, ion-exchange resins, and catalysis
∂t ∂x ∂x
are of very similar nature to a drug diffusing through a macro- or
In Eq. (15), Dip (ci ) is the concentration-dependent diffusion coef- micro-porous polymer. In these types of polymers the diffusion is
ficient; its form of concentration dependence is affected by the assumed to be taking place predominantly through the water, or
structural characteristics of the polymer carrier. body fluid filled pores. The diffusion coefficient of a drug in a poly-
10 J. Siepmann, N.A. Peppas / International Journal of Pharmaceutics 418 (2011) 6–12
Fig. 3. Schematic illustration of a macromolecular network used to control the release rate of a drug. The average molecular weight of the polymer chains between adjacent
crosslinks is denoted M̄c .
mer, Dip , in Eq. (15) is replaced by an effective diffusive coefficient,
Deff , which is defined by Eq. (17) in Table 1. In Eq. (17), ε is the
porosity, or void fraction, of the polymer, which is a measure of
the volume of the pores available for diffusion and  is the tortu-
osity, which describes the geometric characteristics of the pores.
The term Kp is the equilibrium-partitioning coefficient, which is a
parameter, needed when the drug is soluble in the polymer matrix,
it is the ratio of the concentration inside of the pore to the con-
centration outside of the pore. The term Kr describes the fractional
reduction in diffusivity within the pore when the solute diame-
ter, ds , is comparable in size to the pore diameter dr . Eq. (18) in
Table 1 is a semi-empirical relation proposed by Faxen (1923) for
diffusion of spheres through porous media. In this equation,  is
the ratio of the drug radius, rs , to the pore average radius, rp , Dip
and Db are the diffusion coefficients of the sphere through the
pore and in bulk, respectively; and ˛, ˇ and  are constants. It is
clear to see that as the size of the drug gets smaller with respect
to the size of the pore, the ratio of Dip /Db approaches the limit of
one.
Over the past fifty years these equations have been used incor-
rectly to analyze drug transport, especially from tablets. Some of
the common errors are
(1) Use of the equation with a constant diffusion coefficient when
the drug delivery formulation is actually expanding due to
swelling or contracting due significant dissolution and release
of drug with associated pore formation and collapse of the pores
created during the release.
(2) Use of a one-dimensional equation for release from three-
dimensional formulations (such as tablets).
(3) Lack of appreciation of the importance of the lateral area of
diffusion (especially for tablets) and treatment of the problem
as a one-dimensional problem.
(4) While a formulation is swelling or dissolving, the equation used
is one developed with stationary boundary conditions.
(5) Certain contributions ignore the importance of other compo-
nents (e.g., fillers, disintegrants) and treat the drug delivery
process as a one-component diffusion process when in reality
it is a multi-component diffusional process.
An example for a system, which is highly unusual for appli-
cation of Higuchi’s law is illustrated in Fig. 4: Hydroxypropyl
methylcellulose-based tablets containing diltiazem, which are par-
tially coated with an impermeable layer [case 0 (square), case 1
(filled diamond), case 2 (open square), case 3 (open diamond), case
4 (filled square)]. The significant swelling of these systems along
with the impermeable coating layers renders the tablets very spe-
cific and deviate from the Higuchi assumptions.
5. Drug delivery from swellable systems
Transport from swellable systems may often lead to release
under conditions that do not agree with Higuchi’s or the Fickian
behavior (Korsmeyer et al., 1986a,b; Davidson and Peppas, 1986a,b;
Peppas and Korsmeyer, 1987; Lustig and Peppas, 1987; Klier and
Peppas, 1988). For example, a simple semi-empirical equation used
to define water transport in glassy polymers has been proposed
by us (Sinclair and Peppas, 1984). The same equation was further
developed to analyze drug release from films that had both a diffu-
sional and a relaxational component.
For Fickian diffusional release from a thin film, Eq. (14) above
indicates that the first 60% of the normalized drug release at any
time can be characterized by some constant multiplied by the
square root of time. For the second limiting case, Case II water trans-
port and relaxational swelling of a sample, the normalized water
uptake at any time is linearly related to time. Most transport pro-
cesses in glassy polymers fall between these two limiting cases; as
such, they can be represented by a coupling of the Fickian and Case
II transport mechanisms. A simple expression of this observation
can be heuristically written by adding the diffusion-controlled and
relaxation-controlled drug delivery:
Mt √
= k1 t + k2 t (22)
M∞
 J. Siepmann, N.A. Peppas / International Journal of Pharmaceutics 418 (2011) 6–12
Fig. 4. Drug release behavior cannot always be fitted to Higuchi’s law, when var-
ious defining conditions are violated. Here the fractional diltiazem release from
hydroxypropyl methylcellulose-based tablets is presented versus the square root
of release time. The significant swelling of these systems along with the deliberate
partial coating of surfaces of the tablet make this system highly unusual for appli-
cation of Higuchi’s law. The open squares with a dot represent drug release from
uncoated tablets (case 0), the filled diamonds represent drug release from tablets
with one of the bases coated (case 1), the open squares represent drug release from
tablets with both bases coated (case 2), the open diamonds represent drug release
from tablets with the lateral surface coated (case 3), the filled squares represent
drug release from tablets with the lateral surface and one of the bases coated (case
4).
Reprinted with permission from Colombo et al. (1992).
where k1 and k2 are constants. A generalized expression can be
written as:
Mt
= kt n (23)
M∞
11
Table 2
Exponent n of the Peppas equation and drug release mechanism from polymeric
controlled delivery system for different geometries.
Thin film Cylinder Sphere Drug release mechanism
Exponent, n
0.5 0.45 0.43 Fickian diffusion
0.5 < n < 1.0 0.45 < n < 0.89 0.43 < n < 0.85 Anomalous transport
1.0 0.89 0.85 Case-II transport
where k is a constant incorporating characteristics of the
macromolecular network or particle system that makes up the
formulation, and n is the diffusional exponent which is indica-
tive of the transport mechanism. This power law has first been
introduced in the pharmaceutical field in 1985 (Peppas, 1985)
and has become known as the “Peppas equation”. It is valid for
the first 60% of the normalized drug release. In the case of thin
films with negligible edge effects, Fickian drug diffusion and relax-
ational drug transport are defined by n equal to l/2 and n equal to
1, respectively. Anomalous drug transport behavior is intermedi-
ate between Fickian and Case II; this is reflected by the fact that
anomalous behavior is defined by values of n between l/2 and 1.
For other geometries, different n-values are indicative for diffu-
sion or polymer relaxation controlled drug release, as shown in
Table 2.
In recent years, we have seen an explosion in the preparation
and utilization of swellable controlled release systems from simple
nasal, buccal and rectal administration applications to more com-
plex bioadhesive uses. Whether in the form of microspheres, discs
or the more conventional tablets, such systems have now found
applications in various fields. Swellable tablets and related systems
continue being of commercial interest. Several recent studies have
been reported where the releasing area of these systems has been
modified in order to achieve a desirable release rate. Prediction of
release rates from such systems requires expressions of the Fick-
ian or non-Fickian penetrant transport by an appropriate equation,
and similar expression of the drug diffusion. In both cases, the prob-
lem must be solved in a three-dimensional form with appropriate
initial and boundary conditions. This requires extensive numerical
solutions as shown, for example, by Ritger and Peppas (1987b) or
Lustig and Peppas (1989).
6. Conclusions
The classical Higuchi equation had a tremendous impact in the
field of advanced drug delivery and still affects the work of numer-
ous research groups all over the world. Takeru Higuchi can be seen
as the “father” for a mechanistic understanding of controlled drug
delivery systems. His equation allows for a very easy calculation
of drug release from a rather complex type of system. However,
caution should be paid not to violate any of the conditions, the
derivation of this equation is based on.
References
Baker, R., 1987. Controlled Release of Biologically Active Agents. John Wiley & Sons,
New York.
Colombo, P., Catellani, P.L., Peppas, N.A., Maggi, L., Conte, U., 1992. Swelling char-
acteristics of hydrophilic matrices for controlled release: new dimensionless
number to describe the swelling and release behavior. Int. J. Pharm. 88, 99–109.
Crank, J., 1975. The Mathematics of Diffusion. Clarendon Press, Oxford.
Davidson, G.W.R., Peppas, N.A., 1984. The swelling interface number as a criterion
for zero-order release. Proc. Symp. Control. Release Bioact. Mater. 11, 102–103.
Davidson, G.W.R., Peppas, N.A., 1985. Relaxational effects in solute transport and
release from swelling-controlled p(HEMA-co-MMA) systems. Proc. Symp. Con-
trol. Release Bioact. Mater. 12, 25–27.
Davidson, G.W.R., Peppas, N.A., 1986a. Solute and penetrant diffusion in swellable
polymers. V. Relaxation-controlled transport in p(HEMA-co-MMA) copolymers.
J. Control. Release 3, 243–258.
12 J. Siepmann, N.A. Peppas / International Journal of Pharmaceutics 418 (2011) 6–12
Davidson, G.W.R., Peppas, N.A., 1986b. Solute and penetrant diffusion in swellable
polymers. VI. The Deborah and swelling interface numbers as indicators of the
order of biomolecular release. J. Control. Release 3, 259–271.
Eyring, H., 1936. Theory of rate processes. J. Chem. Phys. 4, 283–289.
Faxen, H., 1923. Die Bewegung einer starren Kugel laengs der Achse eines mit zaeher
Flussigkeit gefuellten Rohres. Arch. Mater. Astronom. Fys. 17, 27.
Fick, A., 1855. Ueber diffusion. Poggendorf’s Annalen der Physik 94, 59–86.
Franson, N.M., Peppas, N.A., 1983. Release of drugs from initially glassy, dynamically
swelling p(HEMA-co-MMA) copolymers. Polym. Prep. 24, 53–54.
Fujita, H., 1961. Diffusion in polymer-diluent systems. Fortschr. Hochpolym. –
Forsch. 3, 1–47.
Gurny, R., Doelker, E., Peppas, N.A., 1982. Modelling of sustained release of water-
soluble drugs from porous, hydrophobic polymers. Biomaterials 3, 27–32.
Gurny, R., Doelker, E., Buri, P.A., Korsmeyer, R.W., Peppas, N.A., 1983. Nouvelles
observations sur le mécanisme de libération d’un solute à partir de polymères
hydrophiles. In: Proceed. Congress Intern. Pharmac. Technol. APGI, vol. 3 , pp.
97–105.
Harland, R.S., Gazzaniga, A., Sangalli, M.E., Colombo, P., Peppas, N.A., 1988a.
Drug/polymer matrix swelling and dissolution. Pharm. Res. 5, 488–494.
Harland, R.S., Dubernet, C., Benoit, J.P., Peppas, N.A., 1988b. A model of dissolution-
controlled diffusional drug release from non-swellable polymeric microspheres.
J. Control. Release 7, 207–215.
Harland, R.S., Peppas, N.A., 1989. Solute diffusion in swollen membranes. VII. Diffu-
sion in semicrystalline networks. Colloid Polym. Sci. 267, 218.
Higuchi, T., 1961. Rate of release of medicaments from ointment bases containing
drugs in suspensions. J. Pharm. Sci. 50, 874–875.
Higuchi, T., 1963. Mechanisms of sustained action mediation. Theoretical analysis
of rate of release of solid drugs dispersed in solid matrices. J. Pharm. Sci. 52,
1145–1149.
Klier, J., Peppas, N.A., 1988. Solute and penetrant diffusion in swellable polymers.
VIII. Influence of the swelling interface number on solute concentration profiles
and release. J. Control. Release 7, 61–68.
Korsmeyer, R.W., Rave, T.L., Peppas, N.A., Gurny, R., Doelker, E., Buri, P.A., 1982.
Swelling controlled release systems: progress toward zero-order kinetics with
polymer blends. Proc. Symp. Control. Release Bioact. Mater. 9, 65–68.
Korsmeyer, R.W., Peppas, N.A., 1983a. Macromolecular and modeling aspects of
swelling-controlled systems. In: Roseman, T.J., Mansdorf, S.Z. (Eds.), Controlled
Release Delivery Systems. Dekker, New York, pp. 77–90.
Korsmeyer, R.W., Peppas, N.A., 1983b. Modeling drug release from swellable sys-
tems. Proc. Symp. Control. Release Bioact. Mater. 10, 141–144.
Korsmeyer, R.W., Gurny, R., Doelker, E., Buri, P.A., Peppas, N.A., 1983. Mechanisms
of solute release from porous hydrophilic polymers. Int. J. Pharm. 15, 25–35.
Korsmeyer, R.W., Lustig, S.R., Peppas, N.A., 1986a. Solute and penetrant diffusion in
swellable polymers. I. Mathematical modeling. J. Polym. Sci. Polym. Phys. 24,
395–408.
Korsmeyer, R.W., Meerwall, E.D., von Peppas, N.A., 1986b. Solute and penetrant dif-
fusion in swellable polymers. II. Verification of theoretical models. J. Polym. Sci.
Polym. Phys. 24, 409–434.
Lee, P. Modeling of drug release from matrix systems involving moving
boundaries: approximate analytical solutions. Int. J. Pharm., this issue,
doi:10.1016/j.ijpharm.2011.01.019.
Lustig, S.R., Peppas, N.A., 1984. Scaling concepts in controlled release. Proc. Symp.
Control. Release Bioact. Mater. 11, 104–105.
Lustig, S.R., Peppas, N.A., 1985. The mathematics and physics of solute transport
in continuously swelling hydrophilic polymers. Proc. Symp. Control. Release
Bioact. Mater. 12, 30–31.
Lustig, S.R., Peppas, N.A., 1987. Solute and penetrant diffusion in swellable polymers.
VII. A free-volume-based model with mechanical relaxation. J. Appl. Polym. Sci.
33, 533–549.
Lustig, S.R., Peppas, N.A., 1989. Recent advances in modeling of swelling-controlled
release systems. Proc. Int. Symp. Control. Release Bioact. Mater. 16, 167–168.
Peppas, N.A., 1983. A model of dissolution-controlled solute release from porous
drug-delivery polymeric systems. J. Biomed. Mater. Res. 17, 1079–1087.
Peppas, N.A., Franson, N.M., 1983. The swelling interface number as a criterion for
prediction of diffusional solute release mechanisms in swellable polymers. J.
Polym. Sci. Polym. Phys. 21, 983–997.
Peppas, N.A., Gurny, R., 1983. Relation entre la structure des polymères et la libéra-
tion contrôlée de principes actifs. Pharm. Acta Helv. 58, 2–8.
Peppas, N.A., Reinhart, C.T., 1983. Solute diffusion in swollen membranes. I. A new
theory. J. Membr. Sci. 15, 275–287.
Peppas, N.A., 1984a. Mathematical modelling of diffusion processes in drug delivery
polymeric systems. In: Smolen, V.F., Ball, L.A. (Eds.), Controlled Drug Bioavail-
ability, vol. 1. Drug Product Design and Performance. Wiley, New York, pp.
203–237.
Peppas, N.A., 1984b. Mathematical models for controlled release kinetics. In: Langer,
R.S., Wise, D. (Eds.), Medical Applications of Controlled Release Technology, vol.
2. CRC Press, Boca Raton, Florida, pp. 169–187.
Peppas, N.A., 1984c. Release of bioactive agents from swellable polymers: theory
and experiments. In: Anderson, J.M., Kim, S.W. (Eds.), Recent Advances in Drug
Delivery Systems. Plenum Press, New York, pp. 279–290.
Peppas, N.A., 1984d. Modelling of drug release from porous polymers. Proc. Symp.
Control. Release Bioact. Mater. 11, 94–96.
Peppas, N.A., Sinclair, J.L., Smith, M.J., Mounts, J.G., 1984. Relaxation-controlled
transport of penetrants in glassy polymers. In: Mena, B., Garcia-Rejon, A., Rangel-
Nafaile, C. (Eds.), Advances in Rheology. vol. 3, Polymers. U.N.A.M, Mexico City,
pp. 209–214.
Peppas, N.A., 1985. Analysis of Fickian and non-Fickian drug release from polymers.
Pharm. Acta Helv. 60, 110–111.
Peppas, N.A., Lustig, S.R., 1985. The role of crosslinks, entanglements and relax-
ations of the macromolecular carrier in the diffusional release of biologically
active materials: conceptual and scaling relationships. Ann. N. Y. Acad. Sci. 446,
26–41.
Peppas, N.A., Moynihan, H.J., 1985. Solute diffusion in swollen membranes. IV. The-
ories for moderately swollen networks. J. Appl. Polym. Sci. 30, 2589.
Peppas, N.A., Segot-Chicq, S., 1985. Les dispositifs à libération contrôlée pour la
délivrance des principes actifs médicamenteux. III. Modélisation des mécan-
ismes diffusionnels. STP-Pharma 1, 208–216.
Peppas, N.A., 1987. Swelling controlled release systems: recent developments and
applications. In: Mueller, B.W. (Ed.), Controlled Drug Delivery. Wissenschaftliche
Verlagsgesellschaft, Stuttgart, pp. 160–173.
Peppas, N.A., Korsmeyer, R.W., 1987. Dynamically swelling hydrogels in controlled
release applications. In: Peppas, N.A. (Ed.), Hydrogels in Medicine and Pharmacy,
vol. 3. Properties and Applications. CRC Press, Boca Raton, FL, pp. 109–136.
Peppas, N.A., Sahlin, J.J., 1989. A simple equation for the description of solute release.
III. Coupling of diffusion and relaxation. Int. J. Pharm. 57, 169–172.
Reinhart, C.T., Peppas, N.A., 1984. Solute diffusion in swollen membranes. II. Influ-
ence of crosslinking on diffusive properties. J. Membr. Sci. 18, 227–239.
Ritger, P.L., Peppas, N.A., 1987a. A simple equation for description of solute release. I.
Fickian and non-Fickian release from non-swellable devices in the form of slabs,
spheres, cylinders or discs. J. Control. Release 5, 23–36.
Ritger, P.L., Peppas, N.A., 1987b. A simple equation for description of solute release.
II. Fickian and anomalous release from swellable devices. J. Control. Release 5,
37–42.
Roseman, T.J., Higuchi, W.I., 1970. Release of medroxyprogesterone acetate from a
silicone polymer. J. Pharm. Sci. 59, 353–357.
Siepmann, J., Peppas, N.A., 2000. Hydrophilic matrices for controlled drug delivery:
an improved mathematical model to predict the resulting drug release kinetics
(the “sequential layer” model). Pharm. Res. 17, 1290–1298.
Siepmann, J., Goepferich, A., 2001. Mathematical modeling of bioerodible, polymeric
drug delivery systems. Adv. Drug Deliv. Rev. 48, 229–247.
Siepmann, J., Peppas, N.A., 2001. Modeling of drug release from delivery systems
based on hydroxypropyl methylcellulose (HPMC). Adv. Drug Deliv. Rev. 48,
139–157.
Siepmann, J., Siepmann, F., Florence, A.T., 2006. Local controlled drug delivery to the
brain: mathematical modeling of the underlying mass transport mechanisms.
Int. J. Pharm. 314, 101–119.
Siepmann, J., Siepmann, F., 2008. Mathematical modeling of drug delivery. Int. J.
Pharm. 364, 328–343.
Sinclair, G.W., Peppas, N.A., 1984. Analysis of non-Fickian transport in polymers
using simplified exponential expressions. J. Membr. Sci. 17, 329–331.
Yasuda, H., Lamaze, C.E., 1971. Permselectivity of solutes in homogeneous water-
swollen polymer membranes. J. Macromol. Sci. Phys. B5, 111–134.